PROJECT SUMMARY/ABSTRACT Commensal bacteria in the gut have a significant influence on the development and physiology of the brain, indicating their critical involvement in human neurological disorders. The long-term goal of the proposed research is to obtain a basic understanding of the key molecular and cellular processes responsible for the interactions between the gut microbiota and the brain. The current project is based on unique findings in a Drosophila voltage-gated sodium (Nav) channel mutant Shudderer (Shu). Shu mutants display severe neurological phenotypes including abnormal wing posture, neuronal hyperexcitability, spontaneous tremors and heat-induced seizures. Unexpectedly, these phenotypes were found to be drastically rescued when the mutants were treated with antibiotics. In addition, Shu mutants showed increased innate immune signaling and abnormalities in GABAergic neurons. The fruit flies carry relatively simple commensal bacterial communities and are amenable to versatile genetic approaches, providing a powerful experimental system to uncover the fundamental biological processes important for host/microbiota interactions. The strong microbiota-brain interactions identified in Shu thus offer an exciting opportunity to advance knowledge regarding the roles and action mechanisms for bacteria-dependent modulation of neural function and behavior. Guided by preliminary results, the central hypothesis for the current project is that severity of the neurological phenotype of Shu is increased by particular bacteria species in the gut, which causes aberrant activation of the host immune system to modify neural development and function. This hypothesis will be tested by pursuing the following two specific aims: 1) Determine the effect of particular gut bacteria on severity of the phenotypes of Shu, and 2) Identify the mechanisms by which the gut bacteria modulate the neurological phenotypes of Shu. For Aim 1, Shu mutants mono-associated with particular bacteria species will be generated and their neurological phenotypes will be examined. For Aim 2, immune pathways are genetically manipulated in Shu mutants and the effect on the mutant phenotypes will be investigated. As a consequence of this project, particular bacterial species that significantly exacerbate Shu phenotypes is expected to be identified. A causative relationship between gut bacteria, immune signaling and neural development and/or function is also expected to be revealed. Given that the molecular and cellular mechanisms underlying the basic biological processes are highly conserved between flies and mammals, the proposed study in Drosophila should provide valuable insights into the effect of the gut microbiota on neural development and function in humans. Such new information is expected to contribute to a better understanding of the role of the gut microbiota in etiology and pathophysiology of neurological disorders that are linked to abnormal Nav channel functions, such as epilepsy, autism, migraine, ataxia and pain syndromes, leading to the future development of novel bacteria-related strategies that reduce the burden of patients with these neurological disorders.